Significant advances have been made in the classification and treatment strategies of acute myeloid leukemia (AML) based on karyotype (Mrozek et al., 2000). However, it is clear that cytogenetic translocations, inversions and deletions result in changes at the genetic level which in turn are responsible, at least in part, for malignant transformation (Bloomfield and Caligiuri, 2001). Indeed, consistent molecular abnormalities in the absence of an abnormal karyotype are now starting to emerge in AML with some early evidence for an association with clinical outcome. However, some of these prognostic results, including our own, have been inconsistent. This is likely due to inclusion of factors with confounding prognostic significance, such as age, cytogenetics and variations in treatment within each study. In this proposal, we wish to assess the frequency and predictive value of novel molecular abnormalities in adult AML patients that are enrolled in CALGB treatment protocols (e.g., CALGB 19808 and 10201) and are relatively homogeneous with regard to other important prognostic factors such as cytogenetics, age and treatment. We hypothesize that consistent molecular defects, like certain karyotypes, can be predictive of clinical outcome, can ultimately result in further risk stratification for AML treatment, and can lend insight into treatment approaches for patients with AML. The ultimate goal of the current study is to identify those patients for whom standard therapy will likely result in cure and those patients for whom standard therapy will likely fail, so that therapy can be tailored according to risk, as is currently being done within the CALGB for core binding factor-associated AML. This is a six-year proposal designed to perform definitive analyses on selected pilot studies. The work proposed for CALGB 20202 (which is Project 1 of this LCSC application) follow smaller pilot CALGB studies that are performed and funded by a multitude of investigators using materials from the CALGB Leukemia Tissue Bank (LTB), CALGB 9665. Once these smaller pilot studies are completed and it is determined that they merit further definitive validation, the mechanism described in the current Project 1 will be utilized. As such, this proposal will not attempt to define all the specific analyses to be carried out over the entire six-year funding period, but rather will detail two studies that are currently planned, and provide evidence for the mechanism by which additional studies will be formulated.